tbuckley/cabot-search huggingface dataset:
Abstract 1073: PRMT5 inhibition synergizes with a natural small molecule compound to kill <i>MTAP-</i>deleted cells and suppress tumor growth
Authors: Yasaman Barekatain, Kyle LaBella, Hikaru Sugimoto, Kristen Harris, Sunada Khadka, Florian Muller, Raghu Kalluri
Journal: Cancer Research (2023)

Abstract Homozygous deletion of MTAP occurs in about 15% of all human cancers, such as glioblastoma, pancreatic cancer, mesothelioma, urothelial bladder carcinoma, and lung squamous cell carcinoma. PRMT5 inhibitors show activity against MTAP-deleted cancer cells in culture and xenografts with a mechanism that relies on the significant elevation of the MTAP substrate, methylthioadenosine (MTA). Previously, we have shown that unlike cells in culture, MTA levels in MTAP-deleted primary human GBM tumors are not significantly higher than in MTAP-intact tumors. Therefore, combining the PRMT5 inhibitor with another drug may be required to increase the therapeutic window and clinical efficacy of a PRMT5 inhibitor in MTAP-deleted patients. Here, we identified a natural small molecular chemical compound with a good safety profile that synergizes with a PRMT5-MTA complex inhibitor, which boosts the efficacy of MTAP-deleted selective cell killing in the presence of MTA sequestering cells. This combination therapy significantly increases the potency of PRMT5 inhibitor treatment in MTAP-deleted cells across various tumor cell lines and lowers the IC50 of PRMT5 inhibitor treatment. In vivo, PRMT5 inhibitor combination treatment leads to smaller tumor volumes in MTAP-deleted CDX tumors (U87, glioma cell line) compared to PRMT5 inhibitor monotherapy. In summary, our proposed combination therapy of PRMT5 inhibition with a natural compound may increase the therapeutic window and clinical efficacy of PRMT5 inhibitors leading to better treatment options for patients harboring MTAP-deleted cancer. Citation Format: Yasaman Barekatain, Kyle LaBella, Hikaru Sugimoto, Kristen Harris, Sunada Khadka, Florian Muller, Raghu Kalluri. PRMT5 inhibition synergizes with a natural small molecule compound to kill MTAP-deleted cells and suppress tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1073.
Abstract 4128: AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models
Authors: Vidit Gaur, Anjali Barnwal, Bushra Ateeq, Jayanta Bhattacharyya
Journal: Cancer Research (2023)

Abstract Agonist CD40 antibody (αCD40) has shown excellent anti-tumor efficacy in both pre and early clinical studies. However, in clinics, αCD40 has failed to prove its potential as αCD40 is associated with dose-limiting toxicity due to cytokine release syndrome (CRS), grade 3 to 4 hematological and liver toxicities. In addition, αCD40 induces immune checkpoint proteins (PD-L1, CTLA-4) which makes the tumor microenvironment (TME) immunosuppressive. In this context, this study investigates the therapeutic efficacy of a novel combination of αCD40 and AJ17, a small molecule inhibitor of receptor tyrosine kinase. Combination treatment showed a significant delay in the tumor growth and improved overall survival in mice bearing B16-F10 melanoma and 4T1 orthotopic tumor by increasing the population of CD8+ T cells and lowering the expression of PD-L1, Foxp3+, and arginase in both tumor and spleen. Most interestingly, AJ17 lowered the in vivo toxicity associated with αCD40 monotherapy by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6 in serum. In conclusion, this combination can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while lowering the associated toxicity. Citation Format: Vidit Gaur, Anjali Barnwal, Bushra Ateeq, Jayanta Bhattacharyya. AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4128.
Abstract 4132: Effect of mechanical cues on T cell killing of cancer cells
Authors: Hannah Dada, Kun Do, Alexander Cartagena-Rivera, Grégoire Altan-Bonnet
Journal: Cancer Research (2023)

Abstract Cancer immunotherapies have focused on strategies to strengthen immune cell activation and effector function. These treatment strategies enhance the effector function of immune cells, particularly cytotoxic T cells (CTL), driving tumor eradication. Methods to improve the killing mechanisms of CTLs are not well studied and largely focused on assessing/strengthening the antigenic responses of T cells. We hypothesize that the mechanical landscape of CTL-tumor interactions can also drastically impact CTL cytotoxicity. By altering the physical context for T cell recognition of tumors, we measured cytotoxicity changes and subsequently used these changes in killing capacities to train and generate a quantitative parametrization of T cell killing. CTLs utilize cytokine expression to kill and shape the inflammatory milieu. Taking advantage of a robotic platform that enables the automatic collection of cytokines, we assembled datasets of T cell attacks of tumor cells grown on substrates with varying stiffness levels. The stiffness levels were altered using polyacrylamide (PAA) gels and ranged from 0.2kPa to approximately 113 kPa. Preliminary results from two different models (i.e., mouse and human TCR-transgenic T cells) suggest that there exists an optimal stiffness value for maximal response by T cells. These results suggest that CTLs utilize biophysical cues in addition to molecular cues (antigen) to properly elicit an immune response—modeling and fine-tuning these mechanical cues can be a novel and effective approach to improving cancer immunotherapies. Citation Format: Hannah Dada, Kun Do, Alexander Cartagena-Rivera, Grégoire Altan-Bonnet. Effect of mechanical cues on T cell killing of cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4132.
Abstract 1695: Guanylate binding protein 1 modulate the proteasomal machinery and causes the cytochrome C degradation
Authors: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Sharon J. Pitteri, Sanjay V. Malhotra
Journal: Cancer Research (2023)

Abstract Guanylate Binding Protein 1 (GBP1) is known as an interferon γ induced GTPase. It plays a crucial role in innate immunity against pathogenic infections but its role in cancer and therapeutic response is not well understood. Therefore, to study the role of GBP1, we investigated genetically manipulated ovarian cancer cells. We have employed in vitro and in vivo studies along with a proteomics approach to uncover the protein-protein interactions and their crosstalk with GBP1. The data suggest that GBP1 knockdown (KD) inhibits the clonogenic potential of cancer cells. In vivo studies including subcutaneous xenograft and intraperitoneal models revealed that GBP1 overexpressing (OV) tumor cells growing faster and reduce the median survival of animals compared to vehicle control (VC). Whereas GBP1 KD tumors were progressing slowly with longer median survival compared to scrambled control (SC). To study the molecular interactions of GBP1, we performed a proteomics-based Cellular thermal shift assay (CETSA) on GBP1 OV and KD ovarian cancer cells. We found that GBP1 interacts with members of proteasome including PSMB1, PSMB6, PSMA3, and Cytochrome C (CYCS). Protein analysis showed that GBP1 over-expressing cells had less ubiquitinylated proteins compared to VC, whereas GBP1 KD cells accumulate the ubiquitinylated proteins compared to SC. We also found that the GBP1 KD cells are sensitive to paclitaxel treatment and accumulated ubiquitinylated proteins compared to SC. Moreover, GBP1 KD inhibits the overall proteasomal activity. Paclitaxel-treated GBP1 OV cells accumulated the ubiquitination of CYCS, followed by clearance of cytosolic CYCS. Furthermore, global proteome profiling also suggests that GBP1 KD induces apoptotic pathways whereas GBP1 OV induces pathways associated with the stress response. Overall, the results from our studies elucidate the role of GBP1 in chemotherapeutic stress response via the activation of proteasomal machinery. Citation Format: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Sharon J. Pitteri, Sanjay V. Malhotra. Guanylate binding protein 1 modulate the proteasomal machinery and causes the cytochrome C degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1695.
Abstract 1122: Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs
Authors: E. Alice Lee, Boram Lee, Yoonjoo Choi, Junseok Park, Adam Voshall, Eduardo Maury, Yeeok Kang, Yeon Jeong Kim, Jin-Young Lee, Hye-Ran Shim, Si-Cho Kim, Hoang Bao Khanh Chu, Da-Won Kim, Minjeong Kim, Eun-Ji Choi, Kyungsoo Ha, Jung Kyoon Choi, Yongjoon Kim, Woong-Yang Park
Journal: Cancer Research (2023)

Abstract Transposons comprise half of the human genome and some create novel insertions in human germ cells and somatic tissues of healthy and diseased individuals. These genetic elements may be an abundant yet underexplored source of immunogenic molecules that create chimeric transcripts composed of transposons and non-transposons. However, it remains challenging to accurately identify such transposon-fusion events from short RNA-seq reads mainly due to the repetitive nature of transposon sequences and error-prone read alignment near exon-intron junctions, and there are few existing methods for such detection. We developed a computational pipeline, rTea (RNA Transposable Element Analyzer) to detect transposons-fusion transcripts from RNA-seq data. Using rTea, we performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 2,994 normal tissue samples from the TCGA/ICGC, our unpublished colorectal cancer cohort, and the GTEx consortia. Among normal human tissues, higher fusion loads were found most notably in the testis and to a lesser extent in other tissues that have been characterized as immune-privileged. Somatic fusions found in cancer were enriched in known cancer genes, implicating their contribution to tumorigenesis. We also found distinct epigenetic and tumorigenic mechanisms underlying fusions from different transposon families. Through in silico immunogenicity modeling and experimental validation, we confirmed the MHC-I binding and CD8+ T cell activation by peptides derived from transposon fusions to the extent comparable to EBV viruses. Our findings highlight endogenous retroelements as novel therapeutic targets and a significant source of neoantigens. Citation Format: E. Alice Lee, Boram Lee, Yoonjoo Choi, Junseok Park, Adam Voshall, Eduardo Maury, Yeeok Kang, Yeon Jeong Kim, Jin-Young Lee, Hye-Ran Shim, Si-Cho Kim, Hoang Bao Khanh Chu, Da-Won Kim, Minjeong Kim, Eun-Ji Choi, Kyungsoo Ha, Jung Kyoon Choi, Yongjoon Kim, Woong-Yang Park. Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1122.
Abstract 555: Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells
Authors: Mitomu Kioi
Journal: Cancer Research (2023)

Abstract Background: Local recurrence or lymph node metastasis is one of the critical events for the mortality of patients with oral cancer. Thus, it is essential to elucidate the mechanism of recurrence of oral cancer after treatment. It is recently thought that the cause of recurrence in advanced oral cancer is involvement of microenvironmental changes after treatment and signaling from cancer stem cells. In this study, we aimed to elucidate the molecular mechanism of cancer stem cell signaling that causes microenvironmental changes and the influx of bone marrow-derived cells that lead to revascularization following radiation. Materials and Methods: In order to analyze the function of cancer stem cells, we used YCUOC, a primary tissue obtained from biopsy sample of oral cancer. YCUOC and OSC-19 cell line as a control were inoculated at pre-irradiated site where local blood vessels were eradicated (recurrence model) and non-irradiated sites, and gene expression analysis in cancer tissues was performed. Results: Induction of CD11b-positive bone marrow-derived cells was observed in YCUOC cells, and the higher influx of Tie2-positive cells was observed at the pre-IR site, consistent with activation of HIF-1α. We identified several genes that were up-regulated only in YCUOC at pre-IR site, but neither OSC-19 nor non-IR site. Conclusion: The development of new therapies targeting tumor vasculogenesis is expected by elucidation of cancer stem cell-specific signals. Citation Format: Mitomu Kioi. Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 555.
Abstract 1716: A small molecule corrector for p53 mutants found in cancer
Authors: Maryam Mohammed J Fallatah, Özlem Demir, Rommie Amaro, Peter Kaiser
Journal: Cancer Research (2023)

Abstract p53 is the main tumor suppressor protein in vertebrates and the most frequently mutated gene in human cancers. The majority of p53 mutations are missense mutations resulting in the expression of full-length p53 with inactive tumor suppressor function. Small molecule corrector drugs that change the mutant p53 conformation to a wild-type-like structure are attractive goals for personalized, targeted cancer therapies. Our previous work has shown that restoring p53 activities represses cancer cells and tumor growth in vitro and in vivo. This and other work suggest that reactivation of p53 could have therapeutic potential for cancer patients with mutated p53. This study aims to investigate a new potential p53 corrector small molecule, UCI-1001. Our data suggest that treatment of p53 mutant cancer cell lines with compounds of the UCI-1001 series inhibits cell growth in a p53 mutant-dependent manner and induces some p53-wild-type like activities such as mutant p53 DNA binding, transcriptional activation of p53 target genes, and induction of cell death. Utilizing the cellular thermal shift assay, CETSA, we show that UCI-1001 binds mutant p53 in vivo and changes mutant p53 conformation to a wild-type-like structure. Taken together, these preliminary results suggest the UCI-1001 series is a promising candidate for the development of p53 corrector drugs, but further development of pharmacokinetic properties will be necessary for translation to the bedside. Citation Format: Maryam Mohammed J Fallatah, Özlem Demir, Rommie Amaro, Peter Kaiser. A small molecule corrector for p53 mutants found in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1716.
Abstract 4129: Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682
Authors: Floris L. van Delft, Remon van Geel
Journal: Cancer Research (2023)

Abstract PNU-159,682 is an oxidized secondary metabolite of nemorubicin (MMDX), and substantially more potent (2100-6400-fold) than the commonly used chemotherapeutic anthracycline doxorubicin/adriamycin, but without the dose-limiting cardiotoxicity. Based on these beneficial features, PNU-159,682 is currently being clinically evaluated (phase 1) for solid tumor indications as a payload in various antibody-drug conjugates (NBE-002, SO-N102). It must be noted, however, that the HNSTD of current PNU-based ADCs in non-human primates (~1 mg/kg) may end up in a clinical dose that is sub-optimal to achieve high tumor uptake, due to putative target-mediated drug disposition in healthy tissue. We embarked on a program to develop a set of 2nd-generation PNU-159,682 analogues with attenuated potency, to enable the generation of ADCs with a potentially improved pharmacokinetic profile. Moreover, we reasoned that the adaptation of the new PNU analogues to our proprietary best-in-class ADC technology (GlycoConnect™)1, in combination with our polar spacer technology (HydraSpace™)2 might enable PNU-based ADCs with significantly expanded therapeutic index (TI). We here exhibit the chemical synthesis of a panel of PNU-analogues with attenuated potency and enhanced tolerability, based on specific tailoring of the aminosugar morpholino group. Homogeneous and stable GlycoConnect™/HydraSpace™ ADCs were subsequently generated and evaluated in vitro and in vivo to assess efficacy and tolerability. These studies demonstrate the potential of attenuated PNU derivatives for application in stable and site-specific ADCs with anticipated higher clinic dose and potentially improved therapeutic index. 1 Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14. 2 Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012. Citation Format: Floris L. van Delft, Remon van Geel. Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4129.
Abstract 529: Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M
Authors: Christopher John Occhiuto, Lizbeth Lockwood, Zhilin Hou, Aaron Odom, Karen Liby
Journal: Cancer Research (2023)

Abstract Background: Non-small cell lung (NSCLC) constitutes approximately 80% of all diagnosed cases of lung cancer. Up to 30% of NSCLC acquire mutations that result in constitutive NRF2 pathway activity, which correlates with worse patient prognosis. NRF2 regulates antioxidant genes that confer cytoprotection and chemoresistance. Inhibiting NRF2 activity increases tumor susceptibility to chemotherapy in preclinical lung cancer models; however, there are no FDA-approved NRF2 inhibitors available. Because current inhibitors have low potency and specificity, we developed novel compounds that target the NRF2 pathway. Previously, a high throughput screen identified MSU-38225, which was efficacious in sensitizing chemoresistant lung cancer to chemotherapy in a mouse xenograft model. We sought to improve the poor pharmacokinetics of this compound and developed and characterized a series of novel derivatives with increased solubility. Hypothesis: Derivatives of MSU-38225 inhibit the NRF2 pathway and decrease cancer cell viability. Methods: The efficacy of our NRF2 pathway inhibitors was assessed in A549 and H460 human lung cancer cells with constitutive NRF2 pathway activity using western blotting, RT-PCR, and MTT or Cell Titer Glow viability assays. Cell death and cell cycle analysis were evaluated using flow cytometry. Data were evaluated with one or two-way ANOVA and the Dunnett post-hoc test. Results: The NRF2 pathway inhibitors decreased NRF2 protein level in A549 and H460 cells by approximately 60%, as measured by western blotting. As a result, NRF2-mediated transcription of cytoprotective genes NQO1, GCLC, GCLM, and AKR1C2 were decreased by 30-60% (p&amp;lt;0.05) by qPCR. Further, these compounds decreased lung cancer cell viability, as measured in an MTT assay, by 50% in A549 cells and by 90% in H460 (p&amp;lt;0.05). We then evaluated a specific inhibitor, MSU-71, to determine the cause of decreased viability and found it did not induce annexin-V positive apoptosis. However, subsequent analysis of the cell cycle with propidium iodide univariate analysis showed MSU-71 arrests lung cancer cells. 50% of H460 and 75% of A549 cells were arrested in G2/M (p&amp;lt;0.05). Finally, we developed several “click” chemistry tool compounds that have equitable NRF2 pathway inhibition, which will aid in target identification of the new inhibitors. Conclusion: Taken together, the new NRF2 pathway inhibitors are efficacious in blocking NRF2 activation. Optimization of these inhibitors could lead to a new therapy to treat lung cancer. Citation Format: Christopher John Occhiuto, Lizbeth Lockwood, Zhilin Hou, Aaron Odom, Karen Liby. Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 529.
Abstract 1266: MYC mediated HIF-2α modulates the altruistic stemness reprogramming in leukemia stem cells
Authors: Shirsajit Mitra, Lekhika Pathak, Partha Jyoti Saikia, Bidisha Pal, Bikul Das
Journal: Cancer Research (2023)

Abstract Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction based on stemness genes expression have not yet been identified. Previously, we reported ABCG2, a drug efflux pump, enriches a subpopulation of cells exhibiting a very high level of stemness genes expression in ES cells. These ABCG2+ ES cells exhibited high HIF-2α, which in cooperation with MYC-regulated Nanog and Sox-2. ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibits high level of stemness genes and altruistic behavior. We isolated the ABCG2+ cell subfraction from cervical lymph node and blood of human T-ALL(n=5) and CML(n=7) patients exhibiting high levels of stemness genes in addition to MYC and HIF-2α. We investigated the altruistic stemness phenotype of the ABCG2+ cells by studying the molecular signature of MYC binding to HIF-2α. siRNA HIF-2α treatment led to ABCG2+ cell loss of proliferative capacity and reduced GSH levels, suggesting reduction of cytoprotective altruistic behavior in vitro. Treatment of ABCG2+ cell harboring mice with FM19G11 led to marked loss in the secondary engraftment in NOD/SCID mice, indicating loss of ABCG2+ cell self-renewal capacity. We found siRNA MYC inhibition led to loss of HIF-2α expression, suggesting that MYC might be regulating HIF-2α mediated altruistic stemness program in the ABCG2+ cells. Overall, we found that ABCG2 can be a probable marker to enrich the LSC subfraction having high expression of stemness genes and altruistic stemness phenotype. Citation Format: Shirsajit Mitra, Lekhika Pathak, Partha Jyoti Saikia, Bidisha Pal, Bikul Das. MYC mediated HIF-2α modulates the altruistic stemness reprogramming in leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1266.